Dihydropyrimidine compounds and preparation methods, pharmaceutical compositions and uses thereof

Abstract

Disclosed are dihydropyrimidine compounds and preparation methods, pharmaceutical compositions and uses thereof. Specifically, the compounds described herein in general formula (I), or their isomers, pharmaceutically acceptable salts or hydrates are provided, wherein each variable has the meaning as defined in the description. Also provided are a process for preparing the compounds of the general formula (I), the use of the compounds, an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof as a medicament, in particular as a medicament for the treatment and/or prevention of Hepatitis B.

What is claimed is:  
     
       1. A compound of general formula (I), or an optical isomer, pharmaceutically acceptable salt or hydrate thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 represents a halogen, a nitrogen-containing (C4-C14)-heterocyclic group, a (C1-C6)-alkylamino or a (C1-C6)-alkoxy, in which the nitrogen-containing heterocyclic group and alkyl moiety are optionally substituted by hydroxyl, a (C1-C6)-alkoxy, a (C1-C6)-alkoxycarbonyl, an aryl, a substituted aryl or a (C1-C6)-alkyl; 
 R2, for one or more occurrences, each represents a substituent selected from a halogen, nitro, hydroxyl, sulphonyl, a straight or branched (C1-C6)-alkyl, a (C1-C6)-alkoxyl, a (C1-C6)-alkoxycarbonyl, amino, a mono- or di-substituted amino, or an amido; 
 R3 represents a (C1-C6)-alkyl; and 
 R4 represents a halogen, a nitrogen-containing (C4-C8)-heterocyclic group, a (C1-C6)-alkylamino, a (C1-C6)-alkoxy, or a bi(C1-C6)-alkylamino, in which the nitrogen -containing heterocyclic group and alkyl moiety are optionally substituted by hydroxyl, a (C1-C6)-alkoxy, a (C1-C6)-alkoxycarbonyl, an aryl, a substituted aryl, oxo or a (C1-C6)-alkyl. 
 
     
     
       2. A compound of general formula (Ia), or an optical isomer, pharmaceutically acceptable salt or hydrate thereof, 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 represents a halogen, a nitrogen-containing (C4-C14)-heterocyclic group, a (C1-C6)-alkylamino or a (C1-C6)-alkoxy, in which the nitrogen-containing heterocyclic group and alkyl moiety are optionally substituted by hydroxyl, a (C1-C6)-alkoxy, a (C1-C6)-alkoxycarbonyl, an aryl, a substituted aryl or a (C1-C6)-alkyl; 
 R2, for one or more occurrences, each represents a substituent selected from a halogen, nitro, hydroxyl, sulphonyl, a straight or branched (C1-C6)-alkyl, a (C1-C6)-alkoxyl, a (C1-C6)-alkoxycarbonyl, amino, a mono- or di-substituted amino, or an amido; 
 R3 represents a (C1-C6)-alkyl; and 
 R4 represents a halogen, a nitrogen-containing (C4-C8)-heterocyclic group, a (C1-C6)-alkylamino, a (C1-C6)-alkoxy, or a bi(C1-C6)-alkylamino, in which the nitrogen-containing heterocyclic group and alkyl moiety are optionally substituted by hydroxyl, a (C1-C6) -alkoxy, a (Cl-C6)-alkoxycarbonyl, an aryl, a substituted aryl, oxo or a (Cl-C6)-alkyl. 
 
     
     
       3. The compound according to  claim 1  or  2 , or an optical isomer, pharmaceutically acceptable salt or hydrate thereof, wherein
 R1 represents a halogen, a nitrogen-containing (C4-C8)-heterocyclic group, a (C1-C4)-alkylamino or a (C1-C4)-alkoxy, in which the nitrogen-containing heterocyclic group and alkyl moiety are optionally substituted by hydroxyl, a (C1-C4)-alkoxy, a (C1-C4)-alkoxycarbonyl , an aryl, a substituted aryl or a (C1-C4)-alkyl; 
 R2, for one or more occurrences, each represents a substituent selected from a halogen, nitro, hydroxyl, sulphonyl straight or branched (C1-C4)-alkyl, a (C1-C4)-alkoxyl, a (C1-C4)-alkoxycarbonyl, amino, a mono- or di-substituted amino, or an amido; 
 R3 represents a (C1-C4)-alkyl; and 
 R4 represents a halogen, a nitrogen-containing (C4-C8)-heterocyclic group, a (C1-C4)-alkylamino, a (C1-C4)-alkoxy, or a bi(C1-C4)-alkylamino, in which the nitrogen-containing heterocyclic group and alkyl moiety are optionally substituted by hydroxyl, a (C1-C4)-alkoxy , a (C1-C4)-alkoxycarbonyl, an aryl, a substituted aryl, oxo or a (C1-C4)-alkyl. 
 
     
     
       4. The compound according to  claim 1  or  2 , or an optical isomer, pharmaceutically acceptable salt or hydrate thereof, wherein
 R1 represents fluoro, tetrahydropyrrolyl, hexahydropyridyl, 4-methylpiperidyl, morpholinyl, thiomorpholinyl, 4-methyl piperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, diethanolamino, 4-ethoxylacylpiperazinyl, 3-oxopiperazinyl, methoxy or ethoxy; 
 R2, for one or more occurrences, each represents fluoro, chloro, bromo, iodo, hydroxyl, nitro, methyl, methoxy, amino or acetylamino; 
 R3 represents methyl, ethyl or propyl; and 
 R4 represents chloro, tetrahydropyrrolyl, hexahydropyridyl, 4-methylpiperidyl, morpholinyl, thiomorpholinyl, 4-methyl piperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, diethanolamino, 4-ethoxylacylpiperazinyl or 3-oxopiperazinyl. 
 
     
     
       5. The compound according to  claim 1  or  2 , or an optical isomer, pharmaceutically acceptable salt or hydrate thereof, which compound is selected from:
 (1) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(chloromethyl)- b 1,4 -dihydropyrimidine-5-carboxylate; 
 (2) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(tetrahydropyrrol-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (3) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(hexahydropyridin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (4) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6- (4-methylpiperidin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (5) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6- (morpholin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (6) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6- (thiomorpholin-l-ylmethyl) -1,4-dihydropyrimidine-5-carboxylate; 
 (7) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(4-methyl piperazin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (8) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(4-ethyl piperazin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (9) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(4-propyl piperazin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (10) ethyl 2-[2,4-difluoro-6-(tetrahydropyrrol-1-yl)phenyl]-4-(2-chloro- 4-fluorophenyl)-6-(tetrahydropyrrol-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (11) ethyl 2-[2,4-difluoro-6-(hexahydropyridin-1-yl)phenyl]-4-(2-chlor- 4fluorophenyl)-6-(hexahydropyridin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (12) ethyl 2[2,4-difluoro-6-(4-methylpiperidin-1-yl)phenyl]-4-(2-chlor-4fluorophenyl)-6-(4-methylpiperidin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (13) ethyl 2-[2,4-difluoro-6-(morpholin-1-yl)phenyl]-4-(2-chlor-4fluorophenyl)-6-(morpholin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (14) ethyl 2-[2,4-difluoro-6-(4-methylpiperazin-1-yl)phenyl]-4-(2-chlor- 4fluorophenyl)-6-(4-methylpiperazin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (15) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6diethanolaminomethyl-1,4-dihydropyrimidine-5-carboxylate; 
 (16) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-(4ethoxylacylpiperazin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate; 
 (17) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6-[(3-oxopiperazin-1-yl)methyl]-1,4-dihydropyrimidine-5-carboxylate; and 
 (18) ethyl 2-(2,4,6-trifluorophenyl)-4-(2-chloro-4-fluorophenyl)-6- (morpholin-1-ylmethyl)-1,4-dihydropyrimidine-5-carboxylate hydrochloride. 
 
     
     
       6. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to  claim 1  or  2 , optionally pharmaceutically acceptable carriers, and optionally other pharmaceutically active compounds. 
     
     
       7. A method of treating an acute or chronic infection caused by hepatitis B viruses, comprising administering a subject in need thereof a therapeutically effective amount of the compound according to  claim 1  or  2 .